The ultimate goal of this program is to facilitate cancer treatment by targeting p53. During the first phase of this study it was demonstrated that p53, besides playing an important role in cancer prevention, is also a determinant of radio- and chemosensitivity of normal tissues, thus contributing to severe side effects of cancer therapy. Therefore, p53 was considered a target for therapeutic suppression to reduce cancer treatment side effects. Small molecules, inhibiting p53 function, were isolated by screening chemical libraries that showed radioprotective effect in vivo with no detectable carcinogenic effect, supporting a new therapeutic strategy of reversible suppression of p53-mediated apoptosis during treatment of p53-deficient tumors and, potentially, other stressful conditions involving activation of p53. Furthermore, there is accumulating evidence indicating that p53 through its involvement of cell cycle checkpoint control can facilitate recovery of tumor cells or tumor vascular endothelium playing a role of a treatment resistance gene and suggesting an additional potential therapeutic value of p53 inhibitors. While inhibition of p53-dependent apoptosis could be beneficial to reduce cancer treatment side effects, suppression of p53-dependent growth arrest might be useful in potentiating conventional anti-cancer treatment. Since p53 controls apoptosis and growth arrest through different mechanisms, there is a need in specific inhibitors of each of these activities. So far p53 inhibitors were isolated based on their effect on p53-dependent transactivation. Specific Aim1 is devoted to isolation of a new class of p53 inhibitors specifically suppressing transactivation-independent apoptosis using a new readout system based on lentiviral transduction of p53. Aim 2 is focused on determining the role of p53 response in the tumor stroma in radiation sensitivity of tumors; a potential value of p53 inhibitory approach will be estimated using a combination of genetic and pharmacological repression of p53. In Aim 3, the effects of p53 inhibition on treatment sensitivity of p53 wild type tumors will be analyzed. Aim 4 addresses the safety concerns related to the p53 inhibitory approach and will result in estimation of a potential risk of carcinogenic effects of different classes of p53 inhibitors.